Pregabalin, having the chemical name (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, is a novel calcium channel modulator (a non γ-butyric acid (GABA) receptor agonist or antagonist), which can block voltage-dependent calcium channels and reduce the release of neurotransmitters. Clinically, it is mainly used for the treatment of peripheral neuropathic pain and for the adjunctive treatment of partial-onset seizures. The current dosage form of pregabalin is the immediate release (IR) dosage form in tablets and capsules mostly, with specifications of 25, 50, 75, 100, 150, 200 and 300 mg/capsule (or tablet), and is administered 2-3 times per day.
A sustained-release preparation developed for once daily can improve patients' drug compliance, reduce or prevent dose-related adverse reactions (by reducing maximum blood concentration Cmax), and improve efficacy (by increasing the maintenance time of effective blood concentration). However, there are some problems in developing a dosage form of pregabalin for once daily administration. Since pregabalin is absorbed through the L-amino acid delivery system, it does not show uniform gastrointestinal absorption. Clinical studies indicate that pregabalin is well absorbed in the small intestine and the ascending colon, but is poorly absorbed after the hepatic flexure. This suggests that the average absorption window of pregabalin is six hours or less, and if developed into a conventional sustained-release preparation, the drug will be wasted and cannot exert any effect when it is transferred to the hepatic flexure about 6 hours after administration. Obviously, for a drug having such an absorption window, it is important to design an effective sustained-release preparation that not only releases the drug at a controlled rate, but also retains the drug in the upper gastrointestinal tract for a long time.
Natural compounds have gained more and more attention due to their good biocompatibility and biodegradability, and are used in various fields from medicine and health products to food additives. Alginic acid is a natural polymer present in brown algae or bacteria, and consists of β-D-mannuronate and α-L-guluronate. The natural marine resources are abundant in China, and the output of alginate is at the forefront of the world. Alginate is widely used in the field of pharmaceutical science, because alginate has a carboxyl group that allows it to adapt to different chemical microenvironments. Alginate can form a gel layer at low pH (i.e., in a gastric fluid environment), which can prolong the residence time of the drug in the stomach by using the properties of alginate to form a swelling gel, thereby increasing the absorption window of certain drugs and improving the bioavailability of the drug. Water-soluble alginate and calcium salt present in the tablet simultaneously can quickly form an acid-insoluble gel matrix of calcium alginate with good strength when the tablet is administered orally and contacts gastric juice, and the drug contained therein is slowly released. At the same time, a gastric retention drug delivery system can also prolong the transit time of the drug along the entire length of the gastrointestinal tract by retaining the drug in the stomach, thereby improving the bioavailability of the drug.
Patent application publication no. CN101330907A discloses a sustained-release preparation for once daily oral administration comprising pregabalin, a matrix forming agent and a swelling agent. The preparation induces the gastric retention of pregabalin by size change after swelling. However, the preparation has a certain burst-release effect, which is not conducive for controlling the slow and stable release of the drug. Also, the size of the preparation after rapid swelling is not significantly greater than the diameter of the human pylon's, such that the possibility of passing through the pylorus cannot be excluded depending on patients' respective gastrointestinal conditions, thereby resulting in failure to show sustained release patterns. Another disadvantage is that the matrix rigidity of the preparation is significantly decreased after 24 hours. Patent application publication no. CN103702664A relates to a pregabalin sustained-release tablet having a two-phase controlled-release system, but the scale up is not easy due to the use of the wet granulation process in the preparation procedure, and there is a certain risk of product consistency after the scale up. Patent CN application publication no. 103585098A discloses a controlled-release preparation containing pregabalin and a preparation method thereof. However, since the preparation is not in a form for gastric retention, it may result in the release of pregabalin not only in the upper part of the small intestine (the main absorption site of pregabalin), but also at other sites, such as the lower part of the small intestine.